Common Variable Immunodeficiency Confirmation Flow Panel
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Common variable immunodeficiency (CVID) is the most prevalent primary immunodeficiency with a prevalence of CVID of 1:25,000 to 1:50,000.(1) It has a bimodal presentation with a subset presenting in early childhood and a second set presenting between 15 and 40 years of age or even later. CVID is characterized by hypogammaglobulinemia usually involving most or all of the immunoglobulin (Ig) classes (IgG, IgA, IgM, and IgE), impaired functional antibody responses, and recurrent sinopulmonary infections.(1) B cell numbers are usually normal, although a minority of patients (5%-10%) have very low B cell counts (<1% of peripheral blood leukocytes). It is reasonable to suspect a transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) defect in patients with low to absent IgA, low IgG, and low or normal IgM, along with splenomegaly, autoimmune cytopenias, autoimmune thyroiditis, and tonsillar hypertrophy. In TACI-deficient patients, there may be an increased risk for developing neoplasias such as non-Hodgkin lymphoma or other solid tumors. CD19 defects result in absence of B cells expressing CD19. When an alternative B-cell marker such as CD20 is used, however, B cells can be detected in the blood of these patients. Inducible T-cell costimulator (ICOS)-deficiency results in reduced class-switched memory B-cells.
Of all patients with CVID, 25% to 30% have increased numbers of CD8 T cells and a reduced CD4/CD8 ratio (<1).(1) A subset (5%-10%) exhibit noncaseating, sarcoid-like granulomas in different organs and also tend to develop a progressive T cell deficiency.(1) Patients with mutations in the TACI gene (see below) are particularly prone to developing autoimmune disease, including cytopenias as well as lymphoproliferative disease.
The etiology of CVID is heterogeneous, but recently 4 genetic defects were described that are associated with the CVID phenotype. Specific mutations, all of which are expressed on B cells, have been implicated in the pathogenesis of CVID. These mutations encode for:
-ICOS: inducible costimulator expressed on activated T cells(2)
-TACI: transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor(3)
-BAFF-R: B-cell activating factor belonging to the tumor necrosis factor (TNF) receptor family(5)
Of these, mutations of the gene that encodes TACI, TNFRSF13B (tumor necrosis factor receptor superfamily, member 13B), probably account for about 10% to 15% of all CVID cases.(3) Patients with mutations in the TACI gene are particularly prone to developing autoimmune disease, including cytopenias, as well as lymphoproliferative disease. The other mutations each have been reported in only a handful of patients. The etiopathogenesis is still undefined in more than 75% to 80% of CVID patients.
A BAFF-R defect should be suspected in patients with low to very low class switched and nonswitched memory B cells and very high numbers of transitional B cells (see IABC / B-Cell Phenotyping Screen for Immunodeficiency and Immune Competence Assessment, Blood). Class switching is the process that allows B cells, which possess IgD and IgM on their cell surface as a part of the antigen-binding complex, to produce IgA, IgE, or IgG antibodies. A TACI defect is suspected in patients with low IgA and low IgG with normal to low switched B cells, with autoimmune or lymphoproliferative manifestations or both, and normal B cell responses to mitogens.
Screening for common variable immunodeficiency (CVID)
Identifying defects in TACI and BAFF-R in patients presenting with clinical symptoms and other laboratory features consistent with CVID
Evaluating B cell immune competence by assessing expression of BAFF-R and TACI proteins
Useful for assessing BAFF-R and TACI protein expression and frequency of B cells bearing these receptors. TNFRSF13C (BAFF-R) and TNFRSF13B (TACI) gene mutations have been described in a small subset of patients with humoral immunodeficiencies classified as CVID. The majority of TNFRSF13B mutations preserve TACI protein expression and require genetic testing to identify pathogenic or potentially pathogenic mutations/variants.
BAFF-R is normally expressed on over 95% of B cells, while TACI is expressed on a smaller subset of B cells (3%-70%) and some activated T cells. Expression on B cells increases with B cell activation.
The lack of TACI or BAFF-R surface expression on B cells is suggestive of a potential common variable immunodeficiency (CVID)-associated defect, if other features of CVID are present. The majority of TACI mutations (>95%) preserve protein expression but abrogate protein function, hence the only way to conclusively establish a TACI mutational defect is to perform genetic testing (TACIF / Transmembrane Activator and CAML Interactor [TACI] Gene, Full Gene Analysis).
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
This test should not be ordered serially.
This test should not be ordered for general evaluation of immune competence.
This test is preferable to order ONLY when there is clear evidence for common variable immunodeficiency and/or evidence of dysregulated B cell subsets (which can be obtained through IABCS / B-Cell Phenotyping Profile for Immunodeficiency and Immune Competence Assessment, Blood).
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
Reference values apply to all ages.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Warnatz K, Denz A, Drager R, et al: Severe deficiency of switched memory B cells (CD27+ IgM-IgD-) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease. Blood 2002;99:1544-1551
2. Grimbacher B, Hutloff A, Schlesier M, et al: Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 2003;4(3):261-268
3. Salzer U, Chapel HM, Webster AD, et al: Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet 2005;37(8):820-828
4. van Zelm M, Reisli I, van der Burg M, et al: An antibody-deficiency syndrome due to mutations in the CD19 gene. N Engl J Med 2006;354:1901-1912
5. Warnatz K, Salzer U, Gutenberger S, et al: Finally found: human BAFF-R deficiency causes hypogammaglobulinemia. Clin Immunol 2005;115(Suppl 1):820